Project Summary Hypertension is a major public health problem associated with an increased risk for heart disease and stroke, leading causes of death worldwide. The majority of hypertensive subjects are now obese and many suffer from insulin resistance, but the molecular mechanisms linking cardiovascular and metabolic derangements in this disease are not fully understood. Increasing evidence suggests that the renin-angiotensin system (RAS), in particular overactivity of angiotensin (Ang) II, plays a pathogenic role in both hypertension and insulin resistance in part through modulation of the sympathetic nervous system. More recently, the vasodilatory peptide Ang-(1-7), which opposes Ang II actions, has been implicated in the pathogenesis of hypertension. While Ang-(1-7) lowers blood pressure and improve insulin action in rodents, the precise mechanisms involved in these effects are unclear. In addition, there are limited and contradictory studies in humans, and we propose that this is due to restraint of Ang-(1-7) cardiovascular actions by autonomic buffering mechanisms. We also propose that Ang-(1-7) improves cardiovascular and metabolic function by inhibiting the sympathetic nervous system. Indeed, our preliminary data suggests that plasma Ang-(1-7) levels are reduced in clinical populations with sympathetic activation. Furthermore, this Ang-(1-7) deficiency appears to interact with the sympathetic nervous system to contribute to hypertension and insulin resistance. Based on these findings, we will test the overall hypothesis that Ang-(1-7) lowers blood pressure and improves insulin sensitivity by opposing the sympathetic nervous system. We will use an innovative translational approach to test this hypothesis that combines integrative physiologic and pharmacologic methods in animal and human experimental models. In Aim 1, we will take advantage of the unique characteristics of central and peripheral autonomic failure patients to determine the contribution of sympatholytic and peripheral vasodilatory mechanisms, respectively, to Ang-(1-7) effects in the absence of baroreflex buffering. In Aim 2, we will examine Ang-(1-7) effects on peripheral and hepatic insulin sensitivity in fructose-fed rats, an established animal model of cardio-metabolic syndrome, and whether these effects involve sympathetic inhibition. Finally, in the independent phase, the PI will examine the importance of endogenous Ang-(1-7): sympathetic interactions to cardiovascular and metabolic function in fructose-fed rats. These collective studies will accomplish the PIs short-term research objective to examine interactions between the sympathetic nervous system and Ang-(1-7) for cardiovascular and metabolic regulation. The findings from these studies will improve our understanding of mechanistic pathways of the RAS, and have the potential to advance current concepts in the field of hypertension to improve targeted treatment approaches and outcomes in this disease. These studies logically build upon the PI's translational background in cardiovascular autonomic regulation, and will provide strong training and a research framework to establish an independent and novel area of research. The PI will acquire new expertise and skills in cutting edge methods to assess insulin action in rodents in the mentored phase of this application, to complement her integrative animal and clinical cardiovascular training and to provide the foundation to be an elite investigator with the capabilities to comprehensively investigate cardio-metabolic function. The clinical studies will be performed under the mentorship of Dr. Italo Biaggioni at Vanderbilt University, a world renowned physician scientist with expertise in neural-metabolic interactions, and in autonomic disorders including primary autonomic failure. The PI will receive training in hyperinsulinemic-euglycemic clamps under the co-mentor Dr. David Wasserman, an expert in metabolism with over 20 years of experience in these methods. The PI has also established an outstanding mentoring team with a proven track record of mentorship and scientific expertise in the RAS, experimental and clinical hypertension, autonomic neuroscience, and biostatistics. Thus, these studies will be conducted in the optimal scientific environment with input from highly experienced mentors, access to unique patient populations, state-of-the-art clinical research and animal facilities, and a wealth of institutional resources for career development. Finally, the PI will participate in extramural activities to enhance her progression into an independent investigator including continued service on national physiology, pharmacology and autonomic committees, reviewing for journals and participating in teaching and mentorship opportunities. Overall, this proposal will advance the PIs long-term research and career goals, to establish a translational independent research program focused on the neural mechanisms of hypertension.